Download The Immune System and Infertility

The Immune System and Infertility
Fact Sheet
Australia´s National Infertility Network
02
updated March 2011
Couples trying to have a baby may be frustrated by both a failure to conceive and
a failure to maintain a pregnancy once conception has occurred. Over the past few
decades it has become increasingly apparent that immunological factors make a
substantial contribution to these two clinical problems.
The body’s immune system includes among its functions the ability to distinguish
self from non-self. This ability (probably not as absolute as once believed) is crucial in the recognition of ‘foreign’ or threatening invasion by infection or cancer cells.
In some instances (called autoimmune diseases) the immune system recognises
‘self’, and that recognition leads to inflammation, damage and disease.
Pregnancy is a unique situation in which the placenta (recognisable as ‘non-self’, or
separate from the mother) invades the lining of the womb and is a potential threat
to the well-being of the mother. The mother’s immune system must recognise that
threat, but also respond in such a way that does not eliminate it. The mother’s immune system is critical in establishing the relationship between the mother and the
foetus that allows both to flourish.
The immune system has two main mechanisms: cellular (type 1) and antibody
(type 2). In normal pregnancy, substances
produced by the placenta (particularly
progesterone) cause a shift in how the
mother’s immune system behaves so
that it becomes ‘type 2 dominant’. This is
because type 1 responses are potentially
more dangerous for the pregnancy. This
shift means that some autoimmune diseases that are predominantly cellular such
as rheumatoid arthritis tend to get better
during pregnancy. But it also means that
antibody autoimmune diseases such as Lupus (SLE) can get worse, and specific anti-
bodies can have their own harmful effects
too – on both the placenta and the foetus.
About seven per cent of the population suffer from an autoimmune disease at some
stage in their lives, and some have life-long
autoimmune diseases such as insulin dependent diabetes and rheumatoid arthritis.
is currently impossible to prove in any individual. Anti-ovarian and anti-testicular
antibodies can be detected in the blood of
individuals with ovarian and testicular failure, but the tests are neither sensitive nor
specific (the antibodies are also found in
apparently normal men and women; and
it is not known if they are the cause or effect of the problem) and by the time the
diagnosis is made, it is usually at the stage
of complete ovarian or testicular failure,
when it is too late for treatment.
Failure of the testis or the ovary can result
from autoimmune processes, although it
Sperm antibodies, whose cause is also unknown, may occur in either the male or
Antibodies to the ovary,
testis and sperm
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Fact Sheet
The Immune System and Infertility
female partner, and can be found in the
blood or sexual secretions, or both. The
tests (agglutination, or immobilisation —
using immunobeads) are difficult to carry
out reliably and can only be done at a few
specialist centres. In addition, by examining the ejaculate in the post coital test, one
can get some clues about the interaction
between spermatozoa and female genital
secretions. However in recent years it has
become apparent that the successful treatment of otherwise unexplained infertility
by intrauterine insemination or IVF has
made the identification of these antibodies
often somewhat academic.
In the ejaculate, sperm antibodies can
cause infertility by affecting sperm mobility or binding to the egg, although it
is still unclear what level of antibodies is
significant to warrant treatment. It is now
known that immunosuppressive therapy
(e.g. Prednisolone tablets) does not improve fertility in this situation. Previous
therapies involved washing sperm, followed by artificial insemination or IVF.
However, in the context of otherwise
unexplained infertility the current treatment of choice is ICSI (where a single
sperm is injected into a single egg).
Sperm antibodies in female sexual secretions may also trap spermatozoa and
prevent them from progressing through
the genital tract. There may be instances
of cytotoxic antibodies that actually kill
the spermatozoa. Attempts to prevent
the exposure of the female genital tract
to spermatozoa for a period of some
months by the use of condoms has been
used in the hope that the immune response will diminish and then exposure
will lead to fertilisation before an immune response occurs. Of course this
treatment will frustrate many who are
anxious to conceive as soon as possible.
Immunosuppressive therapy with corticosteroids has been reported anecdotally with some success. Undoubtedly the
most successful treatments are intrauterine insemination or IVF.
Antiphospholipid
syndrome
In the antiphospholipid syndrome (APS),
women have antiphospholipid antibodies measured as either ‘anticardiolipin
antibodies’ or a ‘lupus anticoagulant’. If
these antibodies occur in women with
reproductive failure and no other clinical
problems then this is termed the primary
APS, and if there are other autoimmune
diseases (e.g. systemic lupus erythematosus (SLE) or Sjogren’s syndrome) it is
called the secondary APS.
It is still unclear if antiphospholipid antibodies have an affect on fertility per se. The
antibodies occur in about four per cent of
healthy Australians, and cannot therefore
be used to screen healthy women who
are planning a pregnancy. They are found
more often in women undergoing IVF,
can directly attack placental cells, and are
often used as markers of a possible immunological disorder. But they are most often
assessed in the context of pregnancy loss.
Antiphospholipid antibodies are reliable
predictors of adverse outcome in pregnancy, and are associated with early and
late foetal loss, pregnancy induced hypertension, intrauterine growth retardation, prematurity, and both venous and
arterial thrombosis occurring during
pregnancy. It must, however, be firmly
emphasised that these associations are
not observed in every woman, nor in every pregnancy. They should, however, be
ordered in women with various adverse
outcomes.
For example:
a
b
d
two or more first trimester
pregnancy losses
one or more second trimester loss
repeated or severe pre-eclampsia
f
g
h
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intrauterine growth retardation
thromboembolic disease
in pregnancy
any woman planning a pregnancy
who has a systemic autoimmune disease
Because 25 per cent of APS give positive
results for only anticardiolipin (aCL) or
lupus anticoagulant (LA), it is important
to test for both during investigations.
In general, the higher the level of anticardiolipin antibody or the stronger the
lupus anticoagulant, then the more likely
an adverse outcome. There are, however,
groups of patients with low positive anticardiolipin antibody and borderline lupus anticoagulant and poor obstetric histories so the level alone cannot be relied
upon as a guide.
Some women with phospholipid antibodies will deliver successfully. However, treatment with aspirin 100mg and
clexane 20-40mg a day has proved safe
and effective in women with recurrent
pregnancy loss. It is unknown if such
treatment improves implantation in IVF,
although women with APS undergoing
IVF should still be treated to reduce the
risk of miscarriage. It is also not known
whether or not this therapy reduces the
risk of pre-eclampsia or intrauterine
growth retardation.
Antibodies affecting the
foetus
Another way in which autoimmunity
can affect the foetus is by passive transfer of an antibody that has pathogenic
effects. Examples include neonatal thyrotoxicosis, neonatal lupus and neonatal myasthenia gravis. All improve as
the level of maternal antibody declines.
Women with SLE need screening for
particular antibodies which can cause
foetal heart block and heart failure.
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Fact Sheet
The Immune System and Infertility
Natural killer cells
In recent years, most immunology research has focused on the ‘specific’ immune system which includes T cells
and B cells. Natural killer (NK) cells
are neither, but they are types of white
blood cells (lymphocytes) which are
part of the ‘nonspecific’ or ‘innate’ immune system. It is believed that in evolutionary terms NK cells are amongst the
most primitive elements of the immune
system. Their prime role appears to be
the early detection (surveillance) and
elimination (killing) of cells that are
not recognised as ‘self ’ (e.g. infections
or cancer). Their killing capacity is also
closely linked with cellular or type 1 immunity. As such they are potentially very
threatening to a developing pregnancy.
It is perhaps not surprising that such
an ancient arm of the immune system
is also intimately involved in the most
fundamental aspect of the propagation
of life: reproduction. NK cells are the
main immune cell-type found in the
uterus. Their numbers increase through
the menstrual cycle to peak at the time
of implantation of an embryo. If an
embryo does implant, NK numbers increase further to 70 per cent of all cells.
Uterine NK numbers start to decrease
at 20 weeks of pregnancy and are absent
at the end of pregnancy. NK cells have
receptors that can bind directly with
placental cells, and they produce a range
of potentially dangerous proteins called
type 1 cytokines (including TNF-alpha
and interferon-gamma).
Thus, on the face of it, NK cells are likely
to be intimately involved in the success or failure of embryo implantation,
causing both infertility and miscarriage.
However, it should be emphasised that
it is still unproven that NK cells do actually cause reproductive failure. Evidence
(see below) is still of poor quality and it
is certainly possible that the studies so far
simply describe an ‘association’ between
NK cell activity and reproductive failure
rather that a specific ‘cause-and-effect’.
Interest in NK cell testing was stimulated
by Alan Beer’s group in Chicago who, in
1996, first reported that blood NK levels
were higher in women with reproductive
failure. Since then over 30 publications
have confirmed that finding in women
with recurrent miscarriage, unexplained
infertility and repeated unexplained IVF
failure. Investigators have reported numbers as a percentage of all lymphocytes,
absolute concentration, different subtypes, markers of activation (e.g. CD69)
and bioassays assessing ‘killing activity’.
There have also been studies (requiring
uterine biopsy) assessing uterine NK cell
levels which are also higher in women
with reproductive failure.
But there are important academic criticisms
of those studies:
d
f
the studies have not included adequate control groups
the laboratory tests are difficult and
there has been no consensus on what to
measure (numbers of cells, cell subtypes,
activation status)
g
there has been no consensus on normal or reference ranges for women of
reproductive age
h
the subtype of NK cells found predominantly in the blood (called CD56dim)
is different to that found in the uterus
(called CD56bright), and the relationship
between the two is still not known
j
there is no evidence that NK cells
actually kill placental cells
In spite of these valid criticisms, it is
hard to ignore the evidence that there
is. Furthermore, immunology (whether
involving NK cells or not) is certain to
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be a major factor in reproductive success, and women with unexplained reproductive failure will always be looking
for potential new ways to improve their
chances. Thus, NK cell testing should
be embraced in the context of research.
There is no reason why women should
not be tested as long as they are aware
that both testing and treatment is still
very much ‘experimental’ at the frontiers
of current knowledge.
It is possible that increased NK cell activity is just one of a number of possible
markers of immunological dysfunction.
These might include antiphospholipid
antibodies, antithyroid antibodies, and
other autoimmune disease.
Treatment of immunological
causes of infertility
The only immunological condition
that is widely accepted as a treatable diagnosis is antiphospholipid syndrome
(aspirin and clexane, as above). The diagnosis of ‘high NK cell activity’ would
logically respond to any possible immune suppressive therapy. In pregnancy
those options include:
k
l
m
n
progesterone
clexane
prednisolone
intravenous immunoglobulin (IVIG)
In prescribing any such therapy, the
treating clinician should carefully explain the side effects, and experimental
nature of the treatment. Randomised
trials have shown no benefit in immune
suppression in ‘unexplained reproductive failure’, but there is no evidence so
far in the subgroup of women with high
NK cell activity.
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Fact Sheet
The Immune System and Infertility
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Related Reading
c
Antiphospholipid antibodies
Gatenby PA; Med J Aust 1994, 160:171-72.
Natural killer cells and reproductive failure – theory, practice
and prejudice
b
Rai R, Sacks GP, Trew G; Hum Reprod.
2005;20(5):1123-6
Uterine natural killer cells,
implantation failure and recurrent miscarriage
n
Recurrent miscarriage:
pathophysiology and outcome
m
Carrington B, Sacks G, Regan L; Curr
Opin Obstet Gynecol. 2005;17(6):591-7
An innate view
of human pregnancy
h
Sacks G, Sargent I, Redman C;
Immunol Today. 1999;20(3):114-8
Quenby S, Farquharson R; Reprod
Biomed Online. 2006;13(1):24-8
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